Molecular Analysis of the Interaction between Human PTPN21 and the Oncoprotein E7 from Human Papillomavirus Genotype 18
Hye Seon Lee 1,5, Min Wook Kim 2,3,5, Kyeong Sik Jin 4, Ho-Chul Shin 1, Won Kon Kim2, Sang Chul Lee2, Seung Jun Kim 1,*, Eun-Woo Lee 2,*, and Bonsu Ku 1,*
1Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea, 2Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea, 3Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea, 4Pohang Accelerator Laboratory, Pohang University of Science and Technology, Pohang 37673, Korea, 5These authors contributed equally to this work.
Received August 14, 2020; Revised November 10, 2020; Accepted December 8, 2020.; Published online January 12, 2021.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

Human papillomaviruses (HPVs) cause cellular hyperproliferation-associated abnormalities including cervical cancer. The HPV genome encodes two major viral oncoproteins, E6 and E7, which recruit various host proteins by direct interaction for proteasomal degradation. Recently, we reported the structure of HPV18 E7 conserved region 3 (CR3) bound to the protein tyrosine phosphatase (PTP) domain of PTPN14, a well-defined tumor suppressor, and found that this intermolecular interaction plays a key role in E7-driven transformation and tumorigenesis. In this study, we carried out a molecular analysis of the interaction between CR3 of HPV18 E7 and the PTP domain of PTPN21, a PTP protein that shares high sequence homology with PTPN14 but is putatively oncogenic rather than tumor-suppressive. Through the combined use of biochemical tools, we verified that HPV18 E7 and PTPN21 form a 2:2 complex, with a dissociation constant of 5 nM and a nearly identical binding manner with the HPV18 E7 and PTPN14 complex. Nevertheless, despite the structural similarities, the biological consequences of the E7 interaction were found to differ between the two PTP proteins. Unlike PTPN14, PTPN21 did not appear to be subjected to proteasomal degradation in HPV18-positive HeLa cervical cancer cells. Moreover, knockdown of PTPN21 led to retardation of the migration/invasion of HeLa cells and HPV18 E7-expressing HaCaT keratinocytes, which reflects its protumor activity. In conclusion, the associations of the viral oncoprotein E7 with PTPN14 and PTPN21 are similar at the molecular level but play different physiological roles.
Keywords: CR3, E7, HPV18, human papillomavirus, PTPN21

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